Descriptions of mutational mechanisms that include the specific interactions between environmental factors and metabolic events impinging upon the accurate transmission of DNA sequences from parent to offspring are the long term goal of the studies described. Our molecular and genetic approach to the study of spontaneous mutation mechanisms is expected to reveal the specific properties of DNA sequences and DNA metabolic enzymes critically involved in spontaneous mutagenesis and, thus, lead to the development of mutational theories. These theories provide a paradigm within which the translation of laboratory measurements of mutagenesis can be extended to predictions of mutation in man; predictions that are increasingly demanded in response to the demonstrated presence of mutagens in the human environment and the contribution of mutagenic processes in many areas of human health, most particularly cancer. The genetic system employed is that of bacteriophage T4. The manipulability of the T4 rII genetic system, the wealth of well-characterized T4 enzymes, and our development of methods that permit the comparison of mutant sequences arising as a consequence of in vivo DNA metabolism and in vitro DNA replication, provide powerful tools for the delineation of the molecular basis of spontaneous mutation. Spontaneous mutational spectra will be used to dissect the diversity of mutational mechanisms, whose specific structural intermediates and dependence upon particular metabolic processes will be subsequently defined by genetic and in vitro techniques having even greater resolving power. A detailed exploration of frameshift fidelity of DNA polymerization is planned using in vivo-in vitro comparisons. Particular attention will be focused upon the processivity of DNA replication and polymerase translocation, the processing of Okazaki pieces and the influence of topoisomerases. The specific and the enzymological processes involved in the production of mutation from DNA misalignments in palindromic and repeated DNA sequences will be identified.